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Cancers (Basel). 2018 Nov 16;10(11). pii: E453. doi: 10.3390/cancers10110453.

Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition.

Author information

1
A.C.Camargo Cancer Center, São Paulo 01509-010, Brazil. elizabeth.santanadossantos@gmail.com.
2
Department of Oncology, Center for Translational Oncology, Cancer Institute of the State of São Paulo-ICESP, São Paulo 01246-000, Brazil. elizabeth.santanadossantos@gmail.com.
3
Department of Genetics, Institut Curie, 75005 Paris, France. elizabeth.santanadossantos@gmail.com.
4
Department of Genetics, Institut Curie, 75005 Paris, France. francois.lallemand@curie.fr.
5
Institut Curie, Paris Sciences Lettres Research University, 75230 Paris, France. francois.lallemand@curie.fr.
6
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia. l.burke@uq.edu.au.
7
Department of Genetics, Institut Curie, 75005 Paris, France. dominique.stoppa-lyonnet@curie.fr.
8
Department of Genetics at Institut Curie, Université Paris Descartes, 75006 Paris, France. dominique.stoppa-lyonnet@curie.fr.
9
INSERM U830, Institut Curie, 75248 Paris, France. dominique.stoppa-lyonnet@curie.fr.
10
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia. melissa.brown@uq.edu.au.
11
Department of Genetics, Institut Curie, 75005 Paris, France. sandrine.caputo@curie.fr.
12
Institut Curie, Paris Sciences Lettres Research University, 75230 Paris, France. sandrine.caputo@curie.fr.
13
Institut Gustave Roussy, 94805 Villejuif, France. etienne.rouleau@gustaveroussy.fr.

Abstract

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition.

KEYWORDS:

BRCA1; BRCA2; hereditary breast cancer; hereditary ovarian cancer; non-coding variants; promoter

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